Abstract
Introduction: We investigated the effects of the relative increase in testosterone by dutasteride administration in patients with benign prostatic hyperplasia and hypogonadism on urinary symptoms or androgen-responsive general health.
Methods: Seventy-six patients were enrolled, and were taking 0.5 mg dutasteride daily for 52 weeks. Before and after treatment, all participants underwent blood test, and body mass index, prostate volume (PV), bone mineral density (BMD), post-voiding residual (PVR) volume, and muscle volume were measured. All patients responded to the questionnaires: International prostatic symptom score (IPSS), Overactive Bladder Symptom score (OABSS). Patients were divided into two groups according to the increase rate of total testosterone (TT): group A, ≥20% increase in TT level; group B, <20% increase or decrease.
Results: Baseline TT and free testosterone (FT) levels were significantly lower in group A than group B. Both groups showed marked improvement in PV and PVR. Group A showed significant improvement in IPSS and OABSS with a significant increase of FT level, whereas group B showed no significant change. Dutasteride treatment contributed to a significant increase in BMD in group A.
Conclusions: Dutasteride treatment significantly improved urinary symptoms and BMD in patients with low baseline serum TT and FT levels.
Introduction
Five-alpha reductase inhibitors (5-ARIs), which block the conversion of testosterone to dihydrotestosterone (DHT) via 5-alpha reductase (5-AR), are widely used for treatment of benign prostatic hyperplasia (BPH) [Citation1]. Two isozymes of 5-AR have been identified, of which the type 2 5-AR primarily found in the prostate gland is effectively inhibited by finasteride, contributing to a 70% decrease in serum DHT concentration [Citation2]. Dutasteride inhibits both isoforms of 5-AR, type 1 5-AR (found in the skin, gut, liver, and other tissues) and type 2 5-AR, which decreases serum concentrations of DHT by more than 90% and subsequently reduces prostate volume, thus improving lower urinary tract symptoms (LUTS) and overactive bladder (OAB) caused by BPH [Citation1,Citation3]. Furthermore, the dutasteride-induced decrease in serum DHT level contributes to an increase of approximately 18% in testosterone level [Citation4].
On the other hand, testosterone levels are known to decline with age by 2–3% annually in men, which may result in specific symptoms called late-onset hypogonadism (LOH) syndrome [Citation5]. The widely recognized clinical signs of LOH syndrome are decreases in libido and sexual desire, decreases in muscle mass and strength, decreased bone mineral density (BMD), increased visceral fat, anemia, and deterioration of insulin resistance [Citation5–7]. Testosterone replacement therapy (TRT) improves many of the LOH-associated symptoms and conditions, and its clinical use has increased substantially over the past several years. Prostate volume is known to increase along with the progressive decline in testosterone level from middle age, reflecting the evolution of BPH and LUTS. Some recent studies suggested that testosterone levels may be significantly correlated with LUTS, and that TRT can contribute to improvement of LUTS/OAB in men with LOH syndrome and BPH [Citation8,Citation9].
It is unclear whether the increased testosterone and DHT suppression caused by dutasteride treatment have important effects on other androgen-responsive functions, such as lipid metabolism, muscle, bone, insulin resistance, hemoglobin and sexual function. Hence, the authors conducted the first prospective study to clarify the effects of the increase in testosterone by dutasteride administration for 1 year among patients with BPH and hypogonadism on urinary symptoms or androgen-responsive general health, such as body mass index (BMI), muscle volume, BMD, insulin resistance, lipid metabolism and erectile function.
Methods
Participants
Patients with a clinical diagnosis of BPH and hypogonadism were prospectively enrolled in this study between June 2010 and August 2011. The inclusion criteria were age ≥50 years with a diagnosis of clinical BPH, International Prostatic Symptom Score (IPSS) score >7 and prostate volume (PV) measured by transrectal ultrasonography ≥20 mL [Citation10], and a diagnosis of hypodonadism. A biochemical diagnosis of hypogonadism was made based on the Japanese biochemical criteria as follows: free testosterone (FT)≤8.5 pg/mL, ART is the first choice of treatment for hypogonadism; FT 8.5–11.8 pg/mL, ART is a relative choice [Citation11].
Patients with serum creatinine (Cr) or alanine aminotransferase (ALT) levels more than twice the upper limits of the normal range at the screening visit were excluded from the study. Furthermore, patients with definite neurogenic bladder, prostate cancer and administration of antiandrogen agents, finasteride or testosterone within 6 months were also excluded from the study. In the patients with prostate-specific antigen (PSA) level >4.0 ng/mL, it was the responsibility of investigators to exclude the presence of prostate cancer.
After obtaining written informed consent and with the approval of the ethics committee of Kanazawa University Graduate School of Medicine, 76 patients with a diagnosis of BPH and hypogonadism were enrolled in this study. All patients were given 0.5 mg of dutasteride daily for 52 weeks.
Study protocol
Before and after dutasteride treatment, all participants underwent blood test, including determination of hemoglobin (Hb), low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride (TG), blood sugar (BS), total testosterone (TT) and FT value. Free T value was evaluated based on blood serum collected between 09:00 and 11:00. Separated serum samples were stored at −20 °C until assay, and free T were measured by RIA, using the DPC Free Testosterone Kit (Mitsubishi Kagaku Iatron). Moreover, a complete medical history was taken and physical examination, including measurement of BMI, was performed. Each eligible subject underwent transrectal ultrasonographic examination to determine PV, and post-voiding residual (PVR) volume measurement was performed by abdominal ultrasonographic examination. In addition, all patients responded to questionnaires, including IPSS, Overactive Bladder Symptom score (OABSS) and International Index of Erectile Function-5 (IIEF-5) score. Muscle mass volume was analyzed using a Body Planner™ DF800 (Yamato Biospace Technology, Hyogo, Japan), which can be used to evaluate systemic body muscle in eight phases (0–7). BMD was measured using dual-energy X-ray absorptiometry at the AP lumbar spine (L2–L4), and BMD/young adult mean (YAM) ratio was calculated as a percentage. All study variables were evaluated at baseline and 12-month visit.
Statistical analysis
All patients were divided into two groups according to the rate of increase in TT; patients with ≥20% increase in TT level by dutasteride administration (group A), and patients with <20% increase or decrease of TT level (group B). The backgrounds of each group were compared by Mann–Whitney test. For each group, the changes in parameters were compared by Wilcoxon’s signed rank test, and changes from baseline in the two groups were evaluated using the unpaired t test. All statistical analyses were performed using SPSS™ version 17.0 Medical Model (SPSS Inc., Chicago, IL). In all analyses, p < 0.05 was taken to indicate statistical significance.
Results
Subject characteristics
The clinical characteristics of the subjects are summarized in . The mean age of the patients was 73.2 ± 6.7 years (range 54–90 years), and the mean TT and FT values were 4.60 ± 1.52 (range 1.60–9.50 ng/mL) and 6.01 ± 2.31 pg/mL (range 1.8–10.7 pg/mL), respectively. The mean values of PV and IPSS score were 44.2 ± 20.3 mL and 15.7 ± 7.5, respectively. Sixty-one patients (80%) took alpha-1 blocker, and 10 (13%) were given other medicines including anticholinergic agents. Eight patients (11%) had mono-therapy of dutasteride.
Table 1. Characteristics of the study population.
Dutasteride treatment for 12 months induced a significant reduction of PV with a mean reduction rate of 28.7 ± 18.4%, and subsequently improved urinary symptoms, such as IPSS (from 15.7 ± 7.5 to 13.5 ± 7.7, p = 0.00191), OABSS (from 5.3 ± 3.0 to 4.5 ± 3.0, p = 0.0102) and PVR volume (from 73 ± 73 to 52 ± 62, p = 0.00878). TT and FT values were significantly increased with mean rates of 20.9% ± 30.1% (range −53%–88%) and 27.4% ± 62.7% (range −68%–391%), respectively. Forty-two (55%) patients had an increase ≥20% in TT value (group A), whereas 45% had a smaller increase (<20%) or a decrease in TT value (group B).
Comparisons of study variables and clinical effects of dutasteride in both groups
We classified into two groups according to TT increase rate, and compared the baseline clinical features in groups A and B (). We found that baseline TT and FT levels were significantly lower in group A than in group B (p = 0.00528 and 0.0113, respectively). On the other hand, the other study variables did not differ significantly between the two study groups.
Table 2. Comparisons of study variables between the groups.
After 12 months of dutasteride administration, there were significant reductions in PV and PVR in both groups (p < 0.05) (). FT level showed a significant increase in group A, but a significant decrease in group B. Group A showed significant improvements in IPSS score (from 16.6 ± 7.6 to 13.5 ± 7.9, p < 0.05) and OABSS (from 5.3 ± 3.9 to 4.8 ± 3.2, p < 0.05), with a significant increase in the level of FT, the active form of testosterone, at the 12-month visit, whereas group B showed no significant changes in IPSS or OABSS with a decrease of FT value. In addition, dutasteride treatments over 52 weeks contributed to a slight but significant increase of BMD/YAM ratio in group A (from 105.4 ± 22.1 to 106.5 ± 22.0, p < 0.05), whereas group B showed no significant changes in BMD/YAM ratio. Furthermore, there were no significant decreases in Hb concentration or IIEF5 score in group A, in contrast to the observations in group B. On the other hand, there were no significant changes in any other parameters, such as BMI, muscle volume, BS, LDL, TG and HDL values, over this period in either group. However, comparisons of changes from baseline to 12-month visit showed no significant differences in changes of any parameters, excluding FT level, in the two groups ().
Table 3. Comparison of each parameter between baseline and 12-month visit in the two groups.
Table 4. Comparison of changes from baseline to 12-month visit in the two groups.
Discussion
Though some overseas guidelines have recommended using serum TT value for a diagnosis of LOH syndrome [Citation12,Citation13], we used FT value as a biochemical diagnosis of LOH syndrome according to the Japanese criteria. The International Society for the Study of the Aging Male (ISSAM) also supposed a usage of calculated free T estimated from measured total T and sex hormone-binding globulin (SHBG) values [Citation12]. However, measurement of SHBG has not been approved as in vitro diagnostics in Japan, and is not covered by health insurance, and is therefore not commonly used. In addition, a large population study found that FT value, but not TT value, shows a significant correlation with aging among Japanese men [Citation11]. Favorable correlations (R2 = 0.4238) between calculated free T and free T have been also reported [Citation11]. Thus, the Japanese guideline of LOH syndrome has recommended usage of FT value for a diagnosis.
We found that dutasteride treatment contributed to an approximately 20% increase in serum TT level. Indeed, it is well known that a decrease in serum DHT level by dutasteride administration results in a relative increase in testosterone level. A previous Japanese randomized controlled trial demonstrated that treatment with dutasteride for 24 weeks contributed to an 18.8% mean increase in TT level [Citation14]. Other studies indicated that dutasteride reduced the serum DHT levels from baseline by 84% at 2 weeks and by approximately 90% at 1 month, and that the decrease in DHT level with dutasteride was accompanied by reciprocal increases in the serum and intraprostatic testosterone levels [Citation4,Citation15]. Our results were consistent with previous findings. However, a wide degree of variation in TT increase rate was observed in the present subjects, suggesting that the response of TT level induced by dutasteride administration is not always invariable among hypogonadal men.
We found that 55% of patients (group A) had an increase in TT level ≥20 (group A), and had significant lower levels of baseline TT and FT compared with group B. Hong et al. reported that the mean percentage increase in serum TT level after 1 year of dutasteride treatment was greater (38.6%) in the group with lowest TT level (TT < 3.6 ng/mL) at baseline, followed by 14.2% in the moderate group (TT; 3.6–5.0 ng/mL), and −3.2% in the highest group (TT > 5.0 ng/mL) [Citation16]. Although further studies in larger populations are required, the effects of dutasteride on serum TT level are likely to be variable according to baseline serum TT level, and men with a relatively low TT level at baseline may have a greater increase in TT level by dutasteride treatment.
Little information has been reported to date regarding the potential impacts of dutasteride on androgen-responsive general health factors, such as bone metabolism, muscle, lipoprotein concentration and insulin resistance. In the present study, we conducted a prospective study to investigate the clinical effects of dutasteride by dividing patients into two groups according to TT increase rate, and found some differences in clinical effects of dutasteride according to differences in TT increase level. To our knowledge, there have been few studies of the effects of dutasteride on systemic and urinary symptoms according to TT increase levels.
Remarkable improvements in IPSS and OABSS were observed in group A, in contrast to the observations in group B. As there were no significant changes in PV reduction in either group, TT increase level following dutasteride administration may be directly associated with improvement of urinary symptoms. Indeed, Group A had a greater increase in FT value, active form of testosterone, compared with group B. It is widely known that testosterone deficiency is closely linked to LUTS [Citation17]. Androgen receptors are expressed on the urinary bladder, prostate gland, and urethral mucosa, and testosterone shows direct interactions with the urinary tract [Citation17,Citation18]. Another explanation is that nitric oxide synthase (NOS) gene expression is reduced with aging in prostate tissue, which is involved in the increased smooth muscle tone associated with LUTS [Citation19]. Indirect effects of the interaction of testosterone with NOS present on the urinary tract system may also be associated with LUTS [Citation18]. Alternatively, decreases in bladder blood flow due to pelvic ischemia caused by aging and arterial sclerosis have been demonstrated in patients with BPH and LUTS [Citation20], and some studies suggested that a decrease in blood flow may be associated with the development of LUTS and OAB [Citation21,Citation22]. Testosterone has been shown to interact with endothelial NOS expressed in pelvic vessels, and consequently improve pelvic blood flow [Citation23]. Some recent reports suggested that TRT may contribute to improving LUTS/OAB in men with LOH syndrome and BPH [Citation8,Citation9]. However, whether the greater increase in TT by dutasteride administration may have a potential role in LUTS and OAB under conditions of strongly suppressed DHT level has not been clarified.
We found that dutasteride had no clinically significant effects on BMI, muscle volume or serum values of LDL cholesterol, HDL cholesterol, TG and BS in either group. Group A showed no significant change in Hb concentration, whereas it showed a significant decrease in group B. However, its decrease was within the lower limit of the normal range, which was likely to be left out of clinical consideration. A previous randomized, placebo controlled trial reported the impacts of 1-year administration of finasteride or dutasteride on bone, lipid metabolism, hematopoiesis and sexual function among healthy young men aged 18–55 years [Citation24]. This study indicated that dutasteride had little clinical impact on bone turnover markers and lipoprotein values, such as total cholesterol, HDL cholesterol, TG and Hb concentration. Furthermore, similar studies indicated the clinical impacts of finasteride administration in men with BPH, and its long-term uses was not associated with harmful effects on BMD, bone metabolism, lipid metabolism or hematopoiesis [Citation25–27]. These findings suggested that serum DHT level is unlikely to have a clinically significant effect on muscle volume, hematopoiesis, sugar metabolism or lipid metabolism in eugonadal or hypogonadal men. Indeed, a previous randomized trial on the effect of testosterone supplement with and without dutasteride on several androgen-responsive tissues has reported that conversion of testosterone to DHT was not essential for mediating its anabolic effects on muscle and lipid metabolism [Citation28]. Intratissue DHT concentration may be originally very low relative to testosterone in tissue with low 5-AR activity, such as muscle and bone, and the androgen effects may not attribute to DHT, but to testosterone mainly.
On the other hand, BMD/YAM ratio showed a significant increase in group A, differing from the observations in group B. Testosterone plays a major role in BMD, and the prevalence rates of osteoporosis and bone fracture are greater in hypogonadal men [Citation27,Citation29]. A previous study demonstrated an inverse correlation between finasteride and bone fracture [Citation28]. Although the pathway through which 5-ARIs may act under conditions of strongly suppressed DHT level is not clear, increased testosterone produces this effect by osteoblastic activity directly or through aromatization to estrogen reducing osteoclastic activity [Citation27,Citation30].
However, comparison of changes from baseline to 12-month visit showed no significant differences in changes of any parameter in either group, suggesting that our data do not exclude clinical effects of dutasteride administration for hypogonadal patients with higher baseline TT and FT levels. Positive clinical effects of dutasteride on urinary functions and BMD can be expected, especially in patients with relatively low baseline serum TT and FT levels. On the other hand, TRT could be also directly effective for these patients with low baseline TT and FT levels. However, a randomized study demonstrated that combined treatment with testosterone plus dutasteride reduced PV and prostate specific antigen (PSA) with mean decrease rates of 12% and 35%, respectively, compared to testosterone only which contributes to significant increases of PV and PSA [Citation31]. TRT may be a risk of worsening of LUTS and prostate hypertrophy in hypogonadal men with severe BPH. Thus, the combination of testosterone and dutasteride could be a more safe option for hypogonadism in men with severe BPH that has less stimulatory effect on the prostate gland.
In conclusion, dutasteride treatment in men with BPH and LOH syndrome contributed to significant improvement of their urinary functions and BMD with a greater increase in TT and FT levels among those with relatively low baseline serum TT and FT levels.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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